Project Summary The ability to flexibly adapt to changing circumstance is critical for navigating through the world. In order to effectively use cues from the environment to inform choices and guide decisions, irrelevant cues must be effectively ignored, and often an appropriate response in one situation becomes inappropriate in another. This type of behavior, referred to as set-shifting, represents a form of cognitive flexibility. Chronic stress can impair the ability to set-shift and may be related to the impairments in set-shifting that accompany psychiatric disorders such as schizophrenia or depression. An extensive body of research in humans and in translational animal models has established a critical role for the prefrontal cortex (PFC) in maintaining cognitive flexibility. However, the precise anatomical and information processing characteristics of the neural circuits within the PFC that enable this behavior remain unknown. Through three distinct aims, we propose to leverage powerful imaging techniques to survey the activity of specific populations of prefrontal neurons in a mouse performing a set-shifting task. In Aim 1, we will use advanced computational methods to identify neural populations encoding distinct task features and map their functional connectivity, revealing subnetworks of neurons specialized for encoding particular features of the environment and of the animal?s behavior. In Aim 2, we will build upon these findings by examining the task-related coding properties of projection-specific neuronal populations in mice undergoing chronic stress in order to examine the effect of stress on behaviorally relevant information coding. In Aim 3, which will be completed during the Independent Phase of the funding period, we will extend our investigation of the effects of stress on prefrontal activity by using high-speed imaging to examine the effects of stress on rapid, network-level state. Together, these aims will advance our understanding of the role of the prefrontal cortex in supporting behavior related to cognitive flexibility and of the circuit-level mechanisms by which stress may impair cognitive flexibility in psychiatric illness-related cognitive deficits. By addressing these questions and carrying out the proposed work, the candidate will build both technical and professional skills that will provide a solid foundation for a future career as an independent researcher. The co-mentors, Drs. Liston and Fusi, will supervise the candidate in formal aspects of the experimental methods and the computational biology through regular meetings (see Training Plan) and also advise and support the candidate in the process of securing a faculty position, setting up an independent lab, and securing initial funding. The Advisory Panel, which consists of Drs. Nestler, Paninski and Grosenick, who have extensive experience with the methods outlined in the Research Strategy, will provide consultation on both the conduct and interpretation of the research and on navigating the professional landscape of early- stage research in an academic setting.